Typically Parkinsonian patients are routinely treated with a combination of levodopa (L-DOPA) and a DOPA decarboxylase inhibitor such as carbidopa or benserazide. Unfortunately, after an initial period of satisfactory, smooth and stable clinical benefit from L-DOPA therapy lasting on the average 2-5 years, the condition of many patients deteriorates and they develop complex dose-related as well as unpredictable response fluctuations. The causes of the response fluctuations are probably multiple and complex, but pharmacokinetic problems (primarily faulty absorption of L-DOPA) may play a critical role. There is a correlation between the clinical fluctuations and the oscillations of L-DOPA plasma levels. Many of the problems are a result of the unfavorable pharmacokinetic properties of L-DOPA, i.e. very poor solubility, poor bioavailability and short half-life in vivo.
A typical problem commonly seen with these patients is the "on-off" oscillations in which daily motor activity is dominated by remarkable swings between off hours, when they are severely incapacitated, rigid, unable to move, and sometimes to speak or swallow, to on periods where they are responsive to L-DOPA and can, more or less, perform. The current treatments (apomorphine, lisuride) used to treat patients in the off period are unsatisfactory. Injection of soluble esters of L-DOPA has been proposed as a rescue therapy for patients in the off state or as a therapeutic tool for stabilization of patients with severe motor fluctuations following chronic L-DOPA therapy. The L-DOPA methyl ester has been suggested as a suitable drug for treatment of such patients (U.S. Pat. Nos. 5,017,607; 4,826,875; 4,873,263; 4,663,349; 4,771,073; Juncos, et al., Neurology 37:1742 (1987); and Cooper, et al., J. Pharm. Pharmacol. 39:809 (1987)). However, a metabolic product of L-DOPA methyl ester is methanol which has been shown to be toxic. The release of methanol from methyl esters may not present toxic hazards under conditions of administration of small quantities of parent drug and/or under acute conditions. However, when daily doses could potentially be about 1 gram/day, the theoretical exposure increases to about 4 mg./dl., which is close to the upper permissible limit of occupational exposure. This risk of toxicity becomes more significant when one considers the reduced metabolic clearance rate in the elderly and the reduced hepatic metabolic capability. As the majority of the Parkinsonian patients are elderly, this possible risk of toxicity becomes significant.
A more suitable L-DOPA ester for therapy would be the L-DOPA ethyl ester. However, the current literature indicates that it is not possible to develop the L-DOPA ethyl ester in a form suitable for pharmaceutical use,
"In view of the potential toxicity that might arise from methanol formation the ethyl ester would ideally have been most suitable for assessment in humans. However, the ethyl ester could not be crystallized as its hydrochloride salt because of its hygroscopic potential. The methyl ester was therefore developed for use in humans." Stocci, F. et al, Movement Disorders, 7:249-256, (1992); at p. 254.
L-DOPA ethyl ester is described in the literature as the hydrochloride salt. However, it is difficult to isolate as a crystalline salt and therefore was described as an amorphous solid (Fix, et al., Pharm. Research 6(6):501-505 (1989)) which is not suitable for pharmaceutical use. Cooper, et al., Clinical Neuropharmacology 7:89-98 (1984) note that L-DOPA ethyl ester hydrochloride salt is hygroscopic and difficult to crystallize during synthesis. We have also confirmed its hygroscopic nature and unsuitability for pharmaceutical use. Clearly, a pure, stable, non-hygroscopic form of L-DOPA ethyl ester is needed for pharmaceutical purposes.
Salts and esters of L-DOPA, including the L-DOPA ethyl ester, are mentioned in Patent GB 1342286 for the treatment of alopecia. The only disclosure regarding the nature of the L-DOPA ethyl ester is that it can be prepared from L-DOPA by conventional methods. However, as noted above, preparation of L-DOPA ethyl ester by conventional methods yields a product which is not suitable for pharmaceutical use because of its lack of purity, its hygroscopicity, and its lack of stability.
GB Patent No. 1,364,505 and corresponding U.S. Pat. No. 3,803,120, assigned to Hoffman-La Roche, describe the synthesis of L-DOPA ethyl ester hydrochloride salt and free base. This compound synthesized is used as an intermediate in the synthesis of other compounds and is not characterized in the patent specification. In agreement with the literature (Fix, et al., Pharm. Research 6(6):501-505 (1989); and Cooper, et al., Clin. Neuropharmacol. 1:89-98 (1984)) we have found that the L-DOPA ethyl ester hydrochloride salt synthesized by the methods described in these patents is hygroscopic, not stable, difficult to crystallize, and, as a result, difficult to purify. This material cannot be used for pharmaceutical compositions.
Likewise the L-DOPA ethyl ester free base as prepared in these two patents is impure and not stable and thus also is not suitable for pharmaceutical compositions. At best it can be used as a synthetic intermediate for further chemical synthesis as described in the cited patents.
Two references note the synthesis of racemic ethyl ester. (Ginssberg, et al., Zh. Obshch. Khim. 39:1168-1170 (1969) and Venter, et al., S. Afr. Tydskr. Chem. 31:135-137(1978)). Neither of these references prepare crystalline L-DOPA ethyl ester in a form suitable for pharmaceutical use and certainly there is no teaching or suggestion of the preparation of crystalline L-DOPA-ethyl ester in a form suitable for pharmaceutical use. Both references prepare the material as an intermediate for the synthesis of other materials of interest.